Esophageal cancer, especially squamous cell cancer, carries with it a dismal prognosis as the preponderance of patients present at late stages, thereby defying traditional chemoradiation therapy. Advances in molecular pathogenesis and therapy will provide a foundation for squamous cell cancers at other sites. This is a competing renewal of the NCI P01 entitled Mechanisms of Esophageal Carcinogenesis that has made substantial progress in elucidating the molecular mechanisms underlying squamous cell carcinogenesis with translation to new strategies in therapy. Novel, innovative models have been generated involving 3D organotypic cultures, in vivo bioluminescence imaging in immunodeficient mice and genetically engineered mice that permit recapitulation, for the first time, cardinal genetic features of esophageal squamous cell cancer. New insights have been gained into the esophageal tumor microenvironment, revealing that the interplay between transformed esophageal epithelial cells, mesenchymal stromal fibroblasts and endothelial cells is critical in fostering tumorigenesis. Mechanisms have been identified that underlie resistance to chemoradiation therapy. The experience and expertise of the Project Leaders, in concert with the platforms provided by the Core Facilities, will result in enhancement of the research that would not be possible if the projects were independent of each other. Project 1 (Rustgi, Project Leader) will focus upon the biological roles of the EGFR oncogene and cooperation with p120-catenin and p53 tumor suppressor genes in esophageal carcinogenesis, and the role of activated stromal fibroblasts in augmenting tumor cell invasion in the microenvironment. Project 2 (Herlyn, Project Leader) defines the relationship between fibroblasts and endothelial cells in the tumor microenvironment, and exploits this information to develop new therapeutics. Project 3 (Diehl, Project Leader) elucidates the manner in which cyclin D1 is regulated and defines the novel role of the Fbx4 mutations in esophageal carcinogenesis, with translation into the development of therapeutic approaches. Four highly successful Core facilities are designed to provide esophageal cancer-specific services for the stimulation of collaborative research: Morphology, Molecular Biology, Biostatistics and Administrative. The Program Project has the unequivocal support of the University of Pennsylvania Cancer Center and Medical School (with robus commitment of new resources) and will continue to foster interdisciplinary research at Penn and nationally which leads to a cooperative understating of the molecular processes that form and regulate esophageal carcinogenesis.